Synthesis of polyhydroquinoline derivatives through unsymmetric Hantzsch reaction using organocatalysts

Article abstract of DOI:10.1016/j.tet.2006.12.074

A novel and green approach for efficient and rapid synthesis of polyhydroquinoline derivatives via unsymmetric Hantzsch reaction using organocatalysts at room temperature was reported. The process is a simple, environmentally friendly, rapid, and high yie

Full text of DOI:10.1016/j.tet.2006.12.074

Tetrahedron 63 (2007) 1946–1952
Synthesis of polyhydroquinoline derivatives through
unsymmetric Hantzsch reaction using organocatalysts*
*
Atul Kumar and Ram Awatar Maurya
Medicinal and Process Chemistry Division, Central Drug Research Institute, Lucknow, UP 226001, India
Received 3 November 2006; revised 19 December 2006; accepted 21 December 2006
Available online 28 December 2006
Abstract—A novel and green approach for efficient and rapid synthesis of polyhydroquinoline derivatives via unsymmetric Hantzsch
reaction using organocatalysts at room temperature was reported. The process is a simple, environmentally friendly, rapid, and high yielding
reaction for the synthesis of polyhydroquinoline derivatives. The catalytic efficiency of various small organocatalysts such as L-proline, trans-
4-hydroxy-L-proline, L-thiaproline, DL-phenylglycine, and (ꢀ)-cinchonidine was studied under aqueous, organic, and solvent free conditions.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
refluxing in alcohol.6 However, these methods suffer from
several drawbacks such as long reaction times, use of large
quantities of volatile organic solvents, low yields, and harsh
reaction conditions. Therefore, it is necessary to develop an
efficient and versatile method for the synthesis of these
compounds. Recently several methods have been reported
comprising the use of microwaves, ionic liquids, TMSCl–
NaI, metal triflates, and polymers.7–14 However, the use of
high temperatures, expensive metal precursors, catalysts
that are harmful to environment, and longer reaction times
limit the use of these methods. Therefore, the search for
a better catalyst for the synthesis of polyhydroquinoline
derivatives using less hazardous solvents or solvent free
conditions is of prime importance.
1,4-Dihydropyridyl compounds are well known as calcium
channel modulators and have emerged as one of the most
important classes of drugs for the treatment of cardio-
vascular diseases.1 Cardiovascular agents such as nifedipine,
nicardipine, amlodipine, and other related derivatives are
dihydropyridyl compounds, effective in treatment of hyper-
tension.2 1,4-Dihydropyridine derivatives possess a variety
of biological activities such as vasodilator, bronchodilator,
antiatherosclerotic, antitumor, geroprotective, hepatopro-
tective, and antidiabetic activity.3 Extensive studies have
revealed that these compounds exhibit various medicinal
functions such as neuroprotectant, platelet anti-aggregatory
activity, cerebral antischemic activity in the treatment of
Alzheimer’s disease, and chemosensitizer in tumor therapy.4
These examples clearly indicate the remarkable potential of
novel dihydropyridine derivatives as a source of valuable
drug candidates. Furthermore, the oxidation of these com-
pounds to pyridines has also been extensively studied.5
Thus, the synthesis of this heterocyclic nucleus is of much
importance.
Organic reactions under aqueous medium and solvent free
conditions have attracted much interest from chemists
particularly from the viewpoints of green chemistry. Green
chemistry approaches are significant due to the reduction
in byproducts, a reduction in waste produced, and lowering
of energy costs. The possibility of performing multicompo-
nent reactions under solvent free conditions with a hetero-
geneous catalyst could enhance their efficiency from an
economic as well as ecological point of view. In recent years,
heterogeneous catalysis is having more importance due to
environmental–economic factors.
Numerous methods have been reported for the synthesis of
polyhydroquinoline derivatives because of the biological
importance associated with these compounds. The classical
method involves three-component coupling of an aldehyde
with ethyl acetoacetate and ammonia in acetic acid or by
Small organic molecules like cinchona alkaloids, L-proline,
and its derivatives are readily commercially available cata-
lysts and have been used in various transformations with ex-
cellent yields.15 L-Proline has been found to be very effective
in enamine based direct catalytic asymmetric aldol,16 Man-
nich,17 Michael,18 Diels–Alder,19 a-amination reactions, and
Knoevenagel type reactions.19,20 More recently, proline and
*
CDRI communication no. 7054.
Keywords: Hantzsch reaction; Polyhydroquinoline derivatives; Green
synthesis; Organocatalyst; Multicomponent reaction.
* Corresponding author. Tel.: +91 522 2612411; fax: +91 522 26233405/
938; e-mail: dratulsax@gmail.com
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.12.074

A. Kumar, R. A. Maurya / Tetrahedron 63 (2007) 1946–1952
1947
its derivatives have been used in multicomponent Biginelli
reactions21 under solvent free conditions. We, therefore,
were interested in exploiting the activity of L-proline as
well as other small organocatalysts in the synthesis of poly-
hydroquinoline derivatives through unsymmetric Hantzsch
reaction.
In order to study the generality of the reaction a number of
polyhydroquinoline derivatives were synthesized in high
yields. This method has the ability to tolerate a variety of
other functional groups such as methoxy, hydroxyl, nitro,
halides, olefins, etc. The results of this study are summarized
in Table 1. Both the electron-rich and electron-deficient
aldehydes worked well leading to high yields of product.
We examined the organocatalyzed reaction with other b-di-
carbonyl compounds such as methyl acetoacetate, tert-butyl
acetoacetate, and 2,4-pentanedione, and similar results were
found with these compounds. However, with 2,4-pentane-
dione yields were somewhat lower than the corresponding
esters.
2. Results and discussion
Herein, we would like to report the studies of a facile unsym-
metric Hantzsch condensation in the presence of a hetero-
geneous organocatalyst (4a–4f) at room temperature using
substituted aldehyde (1), dimedone (2), acetoacetate ester
or acetyl acetone (3), and ammonium acetate to produce
polyhydroquinoline derivatives (5) in high yields (Scheme
1). We examined this reaction under three different sets of
reaction conditions: (i) organic solvents, (ii) water, and
(iii) solvent free conditions.
The use of just 10 mol % of L-proline in stirring ethanol is
sufficient to push the reaction forward. Higher amounts of
L-proline did not lead to significant improvement in the yield
of polyhydroquinolines. In stirring ethanol at room tem-
perature the reaction was complete within 2–3 h. Upon
refluxing in ethanol the reaction rate was increased and the
reaction was complete within 1 h, but the yield was not
increased.
R
O
O
R
O
CHO
O
(1)
R2
R1
NH4OAc
(4a-4f), r.t.
We further studied the catalytic efficiency of other organo-
catalysts (Fig. 1) on the unsymmetric Hantzsch reaction.
In all cases the catalyst was taken as 10 mol % and reaction
was done under solvent free conditions. The results of this
study are shown in Table 2. It was observed that the catalytic
R2
+
N
H
R1
O
O
(2)
(5)
(3)
Scheme 1. Organocatalyzed unsymmetric Hantzsch reaction.
In a typical experimental procedure using traditional con-
ditions, a solution of dimedone, a substituted aldehyde,
acetoacetate ester, and ammonium acetate in ethanol was
stirred in the presence of catalytic amount of L-proline
(10 mol %) for a certain period of time required to complete
the reaction (TLC), resulting in the formation of polyhydro-
quinoline. The reaction mixture was then poured into brine
and extracted with ethyl acetate. The organic layer was dried
over anhydrous sodium sulfate and evaporated to give crude
product. The pure product was obtained by crystallization
from methanol. We also carried out reactions without any
catalyst but the polyhydroquinoline derivatives were iso-
lated in poor yields (8–15%) and the major product isolated
was a dimedone aldehyde adduct.
HO
S
COOH
COOH
COOH
N
H
N
H
N
H
(4a) = L-proline
(4b) = L-thiaproline (4c) = trans-4-hydroxy-L-proline
COOCH3
H
N
H
N
HO
(4d) = L-proline methyl ester
H
Ph
H2N
COOH
N
(4e) = DL-2-phenylglycene
(4f) = (-)-cinchonidine
Figure 1. Organocatalysts used for unsymmetric Hantzsch reaction.
Table 1. L-Proline catalyzed synthesis of polyhydroquinoline derivativesa
Entry
R
R1
R2
Productb
EtOH
Yieldc (%)
Water
Yieldc (%)
Solvent free
Time (h)
Yieldc (%)
Time (h)
Time (h)
1
2
3
4
5
6
7
8
C6H5
4-CH3–C6H4
4-(CH3)2N–C6H4
4-Cl–C6H4
3-NO2–C6H4
4-CH3O–C6H4–CH]CH
1-Naphthyl
3,4-Cl2–C6H3
4-CH3–C6H4
3-CH3O–C6H4
4-CH3O–C6H4–CH]CH
C6H5
4-(CH3)2N–C6H4
3-CH3O–C6H4
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
CH3
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OC2H5
OCH3
tOBu
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
2.0
2.0
2.5
2.0
1.5
3.0
2.0
1.5
2.0
2.5
2.5
2.5
2.5
4.0
85
84
86
81
78
79
84
82
85
82
79
78
76
60
3.5
3.5
3.5
4.0
3.0
4.0
3.0
3.0
3.0
3.0
3.0
4.0
4.5
6.0
72
75
79
75
78
68
64
71
65
62
59
61
64
47
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
0.5
95
94
96
91
92
89
94
92
93
92
89
85
88
83
9
10
11
12
13
14
OCH3
tOBu
tOBu
CH3
a
All reactions were carried at room temperature.
Products were characterized by 1H, 13C, IR, and mass spectroscopy.
Isolated yield.
b
c

1948
A. Kumar, R. A. Maurya / Tetrahedron 63 (2007) 1946–1952
Table 2. Study of catalytic efficiency of various organocatalyst over unsym-
metric Hantzsch reactiona
Entry
Catalyst
None
Yieldb (%)
5f
5a
X
COOR
1
2
12
11
N
H
COOH
4a
4b
95
90
89
N
H
secondary amine required
S
COOH
3
4
85
87
Figure 2. Structure–activity study for successful catalysis.
N
H
HO
moiety plays a significant role in the catalysis of the reaction.
DL-Phenylglycine (4e), which has a primary amino group
and (ꢀ)-cinchonidine (4f), which has a tertiary amino group
were used as catalyst but the yields were low. The results
shown in Table 2 clearly indicate that the presence of a
secondary nitrogen is essential for better catalytic activity.
Replacing CH2 (4a) by S (4b) and with CHOH (4c) did
not considerably affect yields. Thus it was concluded that
L-proline (4a) was the best of all the six catalysts. These
results are summarized in Figure 2.
COOH
4c
89
N
H
COOCH3
4d
5
6
61
47
55
45
N
H
Ph
4e
H2N
HO
COOH
N
H
To avoid the use of ecologically suspected organic solvents,
we carried out the reaction under solvent free conditions
and in aqueous medium. Indeed, water is recognized as an
attractive medium for many organic reactions. The reaction
was carried out successfully at room temperature leading to
good-to-high yields of the products using 10 mol % of
L-proline (4a).
4f
7
49
41
H
N
a
Reaction conditions: aldehyde (1 mmol), ethyl acetoacetate (1 mmol), di-
medone (1 mmol), and ammonium acetate (1 mmol), catalyst 10 mol %,
room temperature, solvent free, stir.
b
Isolated yield.
The reaction under solvent free conditions was found to be
the best for the synthesis of polyhydroquinoline derivatives
using 10 mol % of L-proline (4a) and the products were
obtained in excellent yields. In a typical experimental pro-
cedure b-ketoester (1 mmol), aldehyde (1 mmol), dimedone
(1 mmol), ammonium acetate (1 mmol), and L-proline (4a)
10 mol % were ground in a porcelain mortar and the reaction
was complete within half an hour. The reaction time was
decreased and product yield was increased to a remarkable
extent. The reaction of acetyl acetone, 3-methoxybenzalde-
hyde, dimedone, and ammonium acetate in the presence of
effects of 4a, 4b, and 4c were similar, but when 4d, 4e, and 4f
were taken as catalysts, the product yields were decreased.
The results show that the presence of a secondary nitrogen
in the organocatalyst leads to good yields of products.
When the methyl ester of L-proline (4d) was used as the
catalyst the yields of reactions were decreased (94–61%
and 88–55%). This clearly shows that the presence of a
free carboxylic acid at 2-position makes the catalyst more
efficient. It means that acidic hydrogen of carboxylic acid
O
O
OR2
R
H2O
R1
(6)
H2O + AcOH
H2N
O
+
(5)
RCHO
Step 3
NH4OAc
O
L- Proline
Step 2
O
O
R
O
OR2
OR2
R1
O
O
N
H
R1
Step 4
Step 5
Step 6 L- Proline
NH4OAc
RCHO
O
O
R
OR2
H2O
+
H2O + AcOH
R1
(8 )
NH2
O
(7)
Scheme 2. Proposed mechanism for L-proline catalyzed polyhydroquinoline synthesis.

A. Kumar, R. A. Maurya / Tetrahedron 63 (2007) 1946–1952
1949
10 mol % of L-proline (4a) gave 60% yield in ethanol, 47%
in water but under solvent free conditions the yield was 83%.
In the majority of instances, the crude product was so pure
that it was directly subjected to NMR analysis.
to dryness. A crude solid was obtained. The pure product
was obtained through crystallization from methanol.
When reaction mixture was solid: in a typical experimental
procedure aldehyde 1 (1 mmol), dimedone 2 (1 mmol), ace-
toacetate ester 3 (1 mmol), ammonium acetate (1 mmol),
and L-proline (or other organocatalyst) (0.1 mmol) were
taken in a porcelain dish and were ground by a mortar for
2–3 min. Within 10 min the reaction mixture became oily
and within 30 min it became a brown or yellowish solid.
The reaction mixture was poured into brine and extracted
with ethyl acetate. The organic layer was dried over anhy-
drous sodium sulfate and evaporated to dryness. A crude
solid was obtained. The pure product was obtained through
crystallization from methanol.
We propose a mechanism for the L-proline catalyzed syn-
thesis of polyhydroquinolines (Scheme 2). As L-proline is
well known to catalyze aldol and Michael reactions, poly-
hydroquinoline 5 may be formed either through step 1/
step 2/step 3 or through step 4/step 5/step 6. The
role of L-proline comes in steps 1 and 4 where it catalyses
the Knoevenagel type coupling of aldehydes with active
methylene compounds and in steps 3 and 6 where it catalyses
the Michael type addition of intermediates 5, 6 and 7, 8
to give product 5. The isolated products 5 were racemic
mixtures.
4.3. Typical experimental procedure for the synthesis
of Hantzsch polyhydroquinoline derivatives (5) under
aqueous medium
3. Conclusion
In conclusion, we have developed a simple, rapid, efficient,
and green method for the synthesis of a variety of polyhydro-
quinoline derivatives via an improved Hantzsch reaction cat-
alyzed by small organic molecules. The reaction conditions
are mild and the reaction gives excellent yields of products at
room temperature. This method does not involve the use of
volatile organic solvents, and thus, is an environmentally
friendly process.
In a typical experimental procedure aldehyde 1 (1 mmol),
dimedone 2 (1 mmol), acetoacetate ester 3 (1 mmol), ammo-
nium acetate (1 mmol), and L-proline (or other organo-
catalyst) (0.1 mmol) were taken in a 25 ml round bottom
flask and 1 ml water was added to it. A small magnet was
put in R.B. and was stirred until all reactants were consumed
(TLC). The reaction mixture was poured into 10 ml brine
and extracted with ethyl acetate. The organic layer was dried
over anhydrous sodium sulfate and evaporated to dryness. A
crude solid was obtained. The pure product was obtained
through crystallization from methanol.
4. Experimental
4.1. Materials and general
4.4. Typical procedure for the synthesis of Hantzsch
polyhydroquinoline derivatives (5) in ethanol
All the reactions were carried out at room temperature, that
is, 28–32 ꢁC. Unless otherwise specified, all the reagents
were purchased from Sigma–Aldrich Chemical Co, Lancas-
ter and were used directly without further purification. NMR
spectra were obtained using the Brucker DRX-300 and
200 MHz spectrometer. Chemical shifts (d) are given in parts
per million relative to TMS, coupling constants (J) in hertz.
Mass spectra were obtained using JEOL SX-102 (ESI)
instrument. IR spectra were taken on VARIAN FTIR spec-
trometer as KBr pellets. Elemental analysis was preformed
using a Perkin–Elmer Autosystem XL Analyzer. Melting
points were measured using a COMPLAB melting point
apparatus. Reactions were monitored by thin-layer chroma-
tography (TLC) carried out on 0.25 mm silica gel plates
visualized with UV light.
In a typical experimental procedure aldehyde 1 (1 mmol),
dimedone 2 (1 mmol), acetoacetate ester 3 (1 mmol), ammo-
nium acetate (1 mmol), and L-proline (or other organocata-
lyst) (0.1 mmol) were taken in a 25 ml round bottom flask
and 1 ml ethanol was added to it. A small magnet was put
in R.B. and was stirred until all reactants were consumed
(TLC). The reaction mixture was poured into 10 ml brine
and extracted with ethyl acetate. The organic layer was dried
over anhydrous sodium sulfate and evaporated to dryness. A
crude solid was obtained. The pure product was obtained
through crystallization from methanol.
4.4.1. 2,7,7-Trimethyl-5-oxo-4-phenyl-1,4,5,6,7,8-hexa-
hydroquinoline-3-carboxylic acid ethyl ester (5a). Mp:
1
203–204 ꢁC. H NMR (CDCl3, 300 MHz): d 0.94 (s, 3H),
4.2. Typical experimental procedure for the synthesis
of Hantzsch polyhydroquinoline derivatives (5) under
solvent free conditions
1.07 (s, 3H), 1.21 (t, J¼7.1 Hz, 3H), 2.13–2.29 (m, 4H),
2.35 (s, 3H), 4.06 (q, J¼7.1 Hz, 2H), 5.07 (s, 1H), 6.64 (s,
1H), 7.08–7.13 (m, 1H), 7.18–7.23 (m, 2H), 7.28–7.33 (m,
2H). 13C NMR (CDCl3, 75 MHz): d 12.92, 17.96, 25.84,
28.15, 31.38, 35.33, 39.65, 49.50, 58.52, 104.72, 110.70,
124.74, 126.59, 126.72, 142.41, 145.82, 147.47, 166.24,
When the reaction mixture was oily: in a typical experi-
mental procedure aldehyde 1 (1 mmol), dimedone 2
(1 mmol), acetoacetate ester 3 (1 mmol), ammonium acetate
(1 mmol), and L-proline (or other organocatalyst)
(0.1 mmol) were taken in a 25 ml round bottom flask and
was stirred with a magnetic stirrer until all reactants were
consumed (TLC). The reaction mixture was poured into
brine and extracted with ethyl acetate. The organic layer
was dried over anhydrous sodium sulfate and evaporated
194.43. IR (KBr): 3287, 3078, 2963, 1697, 1611 cmꢀ1
.
MS (ESI) m/z (M+H)+ Calculated for C21H26NO3: 340.2.
Found: 340.2. Analysis calculated for C21H25NO3: C,
74.31; H, 7.42; N, 4.13. Found: C, 74.27; H, 7.39; N, 4.08.
4.4.2. 2,7,7-Trimethyl-5-oxo-4-(4-methylphenyl)-
1,4,5,6,7,8-hexahydroquinoline-3-carboxylic acid ethyl

1950
A. Kumar, R. A. Maurya / Tetrahedron 63 (2007) 1946–1952
1
ester (5b). Mp: 260–262 ꢁC. H NMR (CDCl3, 300 MHz):
d 0.95 (s, 3H), 1.07 (s, 3H), 1.21 (t, J¼7.1 Hz, 3H), 2.13–
2.28 (m, 7H), 2.34 (s, 3H), 4.05 (q, J¼7.1 Hz, 2H), 5.03
(s, 1H), 6.66 (s, 1H), 7.00 (d, J¼7.9 Hz, 2H), 7.19 (d,
J¼7.9 Hz, 2H). 13C NMR (CDCl3, 75 MHz): d 12.95,
17.97, 19.75, 25.91, 28.15, 31.38, 34.85, 39.64, 49.53,
58.50, 104.86, 110.71, 126.58, 127.32, 134.09, 142.25,
142.98, 147.46, 166.30, 194.46. IR (KBr): 3276, 3079,
2962, 1703, 1648 cmꢀ1. MS (ESI) m/z (M+H)+ Calculated
for C22H28NO3: 354.2. Found: 354.0. Analysis calculated
for C22H27NO3: C, 74.76; H, 7.70; N, 3.96. Found: C,
74.74; H, 7.65; N, 3.91.
13C NMR (CDCl3, 75 MHz): d 13.08, 18.04, 25.87, 28.39,
31.32, 32.13, 39.76, 49.51, 54.08, 58.54, 102.77, 108.61,
109.56, 119.18, 121.89, 124.98, 125.47, 126.58, 130.89,
143.10, 148.23, 155.10, 166.30, 194.44. IR (KBr): 3301,
2964, 1676, 1602, 1483 cmꢀ1. MS (ESI) m/z (M+H)+ Calcu-
lated for C24H30NO4: 396.2. Found: 396.1. Analysis calcu-
lated for C24H29NO4: C, 72.89; H, 7.39; N, 3.54. Found:
C, 72.78; H, 7.31; N, 3.43.
4.4.7. 2,7,7-Trimethyl-5-oxo-4-(1-naphthyl)-1,4,5,6,7,8-
hexahydroquinoline-3-carboxylic acid ethyl ester (5g).
1
Mp: 198–200 ꢁC. H NMR (CDCl3, 300 MHz): d 1.09 (s,
3H), 1.12 (s, 3H), 1.28 (t, J¼7.1 Hz, 3H), 2.19–2.33 (m,
4H), 2.37 (s, 3H), 3.76 (s, 3H), 4.12–4.25 (m, 2H), 4.71 (d,
J¼6.1 Hz, 1H), 6.16 (dd, J¼16.2 and 6.1 Hz, 1H), 6.45 (s,
1H), 6.58 (d, J¼16.2 Hz, 1H), 6.78–6.87 (m, 2H), 7.11–
7.16 (m, 1H), 7.37 (d, J¼1.3 Hz, 1H). 13C NMR (CDCl3,
75 MHz): d 13.08, 18.04, 25.87, 28.39, 31.32, 32.13,
39.76, 49.51, 54.08, 58.54, 102.77, 108.61, 109.56,
119.18, 121.89, 124.98, 125.47, 126.58, 130.89, 143.10,
148.23, 155.10, 166.30, 194.44. IR (KBr): 3301, 2964,
1676, 1602, 1483 cmꢀ1. MS (ESI) m/z (M+H)+ Calculated
for C24H30NO4: 396.2. Found: 396.1. Analysis calculated
for C24H29NO4: C, 72.89; H, 7.39; N, 3.54. Found: C,
72.78; H, 7.31; N, 3.43.
4.4.3. 2,7,7-Trimethyl-5-oxo-4-(4-dimethylamino phenyl)-
1,4,5,6,7,8-hexahydroquinoline-3-carboxylic acid ethyl
1
ester (5c). Mp: 262–263 ꢁC. H NMR (CDCl3, 300 MHz):
d 0.97 (s, 3H), 1.07 (s, 3H), 1.22 (t, J¼7.1 Hz, 3H), 2.13–
2.35 (m, 4H), 2.60 (s, 3H), 2.87 (s, 6H), 4.05 (q, J¼7.1 Hz,
2H), 5.00 (s, 1H), 6.36 (s, 1H), 6.60 (d, J¼8.6 Hz, 2H),
7.16 (d, J¼8.6 Hz, 2H). 13C NMR (CDCl3, 50 MHz):
d 14.69, 19.66, 27.67, 29.88, 33.03, 35.78, 41.12, 51.23,
60.12, 106.82, 112.60, 112.76, 136.36, 143.61, 149.07,
149.38, 168.19, 196.31. MS (ESI) m/z (M+H)+ Calculated
for C23H31N2O3: 383.2. Found: 383.3. Analysis calculated
for C23H30N2O3: C, 72.22; H, 7.91; N, 7.32. Found: C,
72.18; H, 7.85; N, 7.25.
4.4.8. 2,7,7-Trimethyl-5-oxo-4-(3,4-dichlorophenyl)-
1,4,5,6,7,8-hexahydroquinoline-3-carboxylic acid ethyl
4.4.4. 2,7,7-Trimethyl-5-oxo-4-(4-chlorophenyl)-
1,4,5,6,7,8-hexahydroquinoline-3-carboxylic acid ethyl
1
ester (5h). Mp: 213–215 ꢁC. H NMR (CDCl3, 300 MHz):
1
ester (5d). Mp: 245–246 ꢁC. H NMR (CDCl3, 300 MHz):
d 0.84 (s, 3H), 1.09 (s, 3H), 1.22 (t, J¼7.1 Hz, 3H), 2.14–
2.38 (m, 7H), 4.03 (q, J¼7.1 Hz, 2H), 5.02 (s, 1H), 6.41
(s, 1H), 7.17 (m, 1H), 7.26 (m, 1H), 7.36 (d, J¼2.0 Hz,
1H). 13C NMR (CDCl3, 50 MHz): d 14.59, 19.85, 27.56,
29.75, 33.14, 36.71, 41.41, 51.02, 60.43, 105.65, 111.76,
128.14, 130.19, 130.41, 132.16, 144.43, 147.70, 148.94,
167.40, 195.90. IR (KBr): 3283, 3078, 2962, 1708, 1650,
1603, 1491 cmꢀ1. MS (ESI) m/z (M+H)+ Calculated for
C21H24Cl2NO3: 408.11. Found: 408.1. Analysis calculated
for C21H23Cl2NO3: C, 61.77; H, 5.68; N, 3.43. Found: C,
61.65; H, 5.56; N, 3.37.
d 0.94 (s, 3H), 1.08 (s, 3H), 1.18 (t, J¼7.1 Hz, 3H), 2.12–
2.34 (m, 4H), 2.37 (s, 3H), 4.04 (q, J¼7.1 Hz, 2H), 5.04
(s, 1H), 6.46 (s, 1H), 7.15–7.19 (m, 2H), 7.24–7.26 (m,
2H). 13C NMR (CDCl3, 75 MHz): d 12.92, 18.05, 25.80,
28.13, 31.39, 34.97, 39.69, 49.42, 58.62, 104.42, 110.46,
126.40, 128.14, 130.32, 142.49, 144.34, 147.26, 165.98,
194.32. IR (KBr): 3276, 3199, 3077, 2964, 1707, 1648,
1604 cmꢀ1
.
MS (ESI) m/z (M+H)+ Calculated for
C21H25ClNO3: 374.1. Found: 374.1. Analysis calculated
for C21H24ClNO3: C, 67.46; H, 6.47; N, 3.75. Found: C,
67.43; H, 6.49; N, 3.69.
4.4.9. 2,7,7-Trimethyl-5-oxo-4-(4-methylphenyl)-
1,4,5,6,7,8-hexahydroquinoline-3-carboxylic acid methyl
ester (5i). Mp: >270 ꢁC. 1H NMR (CDCl3, 300 MHz):
d 0.96 (s, 3H), 1.09 (s, 3H), 2.15–2.38 (m, 10H), 3.62 (s,
3H), 5.04 (s, 1H), 5.96 (s, 1H), 7.00 (d, J¼7.9 Hz, 2H),
7.19 (d, J¼7.9 Hz, 2H). 13C NMR (DMSO-d6, 75 MHz):
d 17.45, 19.73, 25.64, 28.32, 31.30, 34.38, 49.46, 49.78,
102.62, 109.32, 126.36, 127.57, 133.74, 143.82, 144.22,
148.54, 166.56, 193.46. IR (KBr): 3283, 3192, 3071, 2956,
1687, 1602, 1491 cmꢀ1. MS (ESI) m/z (M+H)+ Calculated
for C21H26NO3: 340.2. Found: 340.1. Analysis calculated
for C21H25NO3: C, 74.31; H, 7.42; N, 4.13. Found: C,
74.22; H, 7.35; N, 4.03.
4.4.5. 2,7,7-Trimethyl-5-oxo-4-(3-nitrophenyl)-
1,4,5,6,7,8-hexahydroquinoline-3-carboxylic acid ethyl
1
ester (5e). Mp: 177–178 ꢁC. H NMR (CDCl3, 300 MHz):
d 0.93 (s, 3H), 1.08 (s, 3H), 1.22 (t, J¼7.1 Hz, 3H), 2.12–
2.42 (m, 7H), 3.69 (q, J¼7.1 Hz, 2H), 5.16 (s, 1H), 6.85
(s, 1H), 7.36 (t, J¼7.9 Hz, 1H), 7.71 (d, J¼7.9 Hz, 1H),
7.97 (m, 1H), 7.99 (m, 1H). 13C NMR (CDCl3, 75 MHz):
d 12.90, 18.04, 25.78, 28.09, 31.45, 35.72, 39.54, 49.31,
58.79, 103.71, 109.78, 119.99, 121.59, 127.33, 133.50,
143.42, 146.94, 148.06, 165.72, 194.39. IR (KBr): 3284,
3211, 3079, 2960, 1705, 1607, 1532 cmꢀ1. MS (ESI) m/z
(M+H)+ Calculated for C21H25N2O5: 385.2. Found: 385.1.
4.4.6. 2,7,7-Trimethyl-5-oxo-4-(4-methoxycinnamyl)-
1,4,5,6,7,8-hexahydroquinoline-3-carboxylic acid ethyl
4.4.10. 2,7,7-Trimethyl-5-oxo-4-(3-methoxyphenyl)-
1,4,5,6,7,8-hexahydroquinoline-3-carboxylic acid tert-
butyl ester (5j). Mp: 190–191 ꢁC. 1H NMR (CDCl3,
300 MHz): d 0.96 (s, 3H), 1.08 (s, 3H), 1.38 (s, 9H), 2.14–
2.35 (m, 7H), 3.78 (s, 3H), 4.98 (s, 1H), 5.86 (s, 1H), 6.65
(m, 1H), 6.88 (m, 2H), 7.10 (m, 1H). 13C NMR (CDCl3,
75 MHz): d 17.73, 26.90, 26.99, 28.10, 31.30, 35.82,
39.42, 49.58, 53.75, 78.55, 105.98, 109.58, 110.06,
1
ester (5f). Mp: 198–200 ꢁC. H NMR (CDCl3, 300 MHz):
d 1.09 (s, 3H), 1.12 (s, 3H), 1.28 (t, J¼7.1 Hz, 3H), 2.19–
2.33 (m, 4H), 2.37 (s, 3H), 3.76 (s, 3H), 4.12–4.25 (m,
2H), 4.71 (d, J¼6.1 Hz, 1H), 6.16 (dd, J¼16.2, and
6.1 Hz, 1H), 6.45 (s, 1H), 6.58 (d, J¼16.2 Hz, 1H), 6.78–
6.87 (m, 2H), 7.11–7.16 (m, 1H), 7.37 (d, J¼1.3 Hz, 1H).

A. Kumar, R. A. Maurya / Tetrahedron 63 (2007) 1946–1952
1951
112.95, 119.43, 127.32, 141.57, 147.66, 148.31, 157.94,
165.71, 194.57. IR (KBr): 3292, 3224, 3087, 2958, 1699,
1605, 1491 cmꢀ1. MS (ESI) m/z (M+H)+ Calculated for
C24H32NO4: 398.2. Found: 398.0. Analysis calculated for
C24H31NO4: C, 72.52; H, 7.86; N, 3.52. Found: C, 72.38;
H, 7.76; N, 3.41.
for C21H25NO3: C, 74.31; H, 7.42; N, 4.13. Found: C,
74.25; H, 7.33; N, 4.06.
Acknowledgements
One of the authors, R.A.M., is thankful to CSIR New Delhi
for financial support in the form of a junior research fellow-
ship.
4.4.11. 2,7,7-Trimethyl-5-oxo-4-(4-methoxycinnamyl)-
1,4,5,6,7,8-hexahydroquinoline-3-carboxylic acid methyl
1
ester (5k). Mp: 207–208 ꢁC. H NMR (CDCl3, 300 MHz):
d 1.10 (s, 3H), 1.13 (s, 3H), 2.20–2.38 (m, 7H), 3.72 (s,
3H), 3.76 (s, 3H), 4.69 (d, J¼5.8 Hz, 1H), 6.19 (dd,
J¼16.1 and 5.9 Hz, 1H), 6.36 (s, 1H), 6.55 (d, J¼16.4 Hz,
1H), 6.78–6.87 (m, 2H), 7.12–7.16 (m, 1H), 7.36 (d,
J¼1.4 Hz, 1H). 13C NMR (CDCl3, 75 MHz): d 18.05,
25.90, 28.38, 31.34, 31.91, 39.80, 49.49, 49.82, 54.16,
102.46, 108.80, 109.66, 119.23, 121.80, 125.03, 125.47,
126.60, 130.88, 143.38, 148.03, 155.09, 166.73, 194.38.
IR (KBr): 3297, 3080, 2948, 1681, 1604, 1485 cmꢀ1. MS
(ESI) m/z (M+H)+ Calculated for C23H28NO4: 382.2. Found:
382.3. Analysis calculated for C23H27NO4: C, 72.42; H,
7.13; N, 3.67. Found: C, 72.35; H, 7.02; N, 3.59.
Supplementary data
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2006.12.074.
References and notes
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1
Mp: 222–223 ꢁC. H NMR (CDCl3, 300 MHz): d 0.93 (s,
3H), 1.07 (s, 3H), 1.37 (s, 9H), 2.11–2.27 (m, 4H), 2.32 (s,
3H), 4.99 (s, 1H), 6.43 (s, 1H), 7.07 (t, J¼7.1 Hz, 1H),
7.18–7.23 (m, 2H), 7.28–7.32 (m, 2H). 13C NMR (CDCl3,
75 MHz): d 17.84, 25.92, 26.91, 28.05, 31.36, 35.90,
39.74, 49.53, 78.60, 106.34, 110.60, 124.59, 126.45,
126.85, 141.14, 145.92, 147.29, 165.62, 194.32. IR (KBr):
3280, 3216, 3084, 2965, 1678, 1608, 1491 cmꢀ1. MS
(ESI) m/z (M+H)+ Calculated for C23H30NO3: 368.2. Found:
368.0. Analysis calculated for C23H29NO3: C, 75.17; H,
7.95; N, 3.81. Found: C, 75.14; H, 7.89; N, 3.72.
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phenyl)-1,4,5,6,7,8-hexahydroquinoline-3-carboxylic
acid tert-butyl ester (5m). Mp: 239–240 ꢁC. 1H NMR
(CDCl3, 300 MHz): d 0.94 (s, 3H), 1.05 (s, 3H), 1.39 (s,
9H), 2.11–2.24 (m, 7H), 2.86 (s, 6H), 4.88 (s, 1H), 6.42 (s,
1H), 6.58 (m, 2H), 7.14 (m, 2H). 13C NMR (CDCl3,
50 MHz): d 19.60, 27.80, 28.09, 28.68, 29.76, 33.07,
36.31, 41.27, 41.42, 51.22, 80.13, 108.46, 112.61, 112.86,
129.08, 136.62, 142.22, 148.63, 149.36, 167.61, 196.17.
IR (KBr): 3200, 3077, 2966, 2809, 1688, 1606,
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1520 cmꢀ1
.
MS (ESI) m/z (M+H)+ Calculated for
C25H35N2O3: 411.2. Found: 411.2. Analysis calculated for
C25H34N2O3: C, 73.14; H, 8.35; N, 6.82. Found: C, 73.02;
H, 8.23; N, 6.68.
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3-acetyl-1,4,5,6,7,8-hexahydroquinoline (5n). Mp: 205–
1
206 ꢁC. H NMR (CDCl3, 300 MHz): d 0.88 (s, 3H), 1.07
(s, 3H), 2.16–2.39 (m, 10H), 3.49 (s, 3H), 5.08 (s, 1H),
6.29 (s, 1H), 6.68 (m, 1H), 6.87 (m, 2H), 7.13 (m, 1H).
13C NMR (CDCl3, 75 MHz): d 17.15, 18.95, 25.81, 27.99,
28.32, 31.43, 35.75, 39.79, 49.46, 53.84, 57.17, 110.00,
111.33, 111.67, 112.69, 119.08, 127.99, 142.05, 146.03,
146.51, 158.32, 194.36, 198.00. IR (KBr): 3282, 2954,
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for C21H26NO3: 340.2. Found: 340.1. Analysis calculated
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